Insulin resistance: The central node of convergence between unfolded protein response, diabetes, and cancer

Modern lifestyle patterns, characterized by high-calorie diets and sedentary behaviour, have driven a global surge in obesity, which is a primary driver of insulin resistance (IR) and type 2 diabetes mellitus (T2D). Initially, pancreatic β-cells adapt to IR by increasing proliferation, neogenesis, and insulin secretion to maintain normoglycemia. Also, a prolonged exposure to genetic and environmental stress compromises the β-cell functioning and survival, leading to chronic hyperglycaemia. Beyond its central role in T2D, IR and its metabolic hallmarks, such as hyperinsulinemia, hyperglycaemia, dyslipidaemia, and chronic inflammation, are increasingly linked to heightened cancer risk and adverse outcomes in breast, colon, pancreatic, liver, bladder, and endometrial cancers. Aberrant insulin/IGF signalling, enhanced oxidative stress, inflammatory cytokines, and metabolic reprogramming are key molecular mediators of cancer progression. At the organelle level, both endoplasmic reticulum (ER) and mitochondria, and their functional crosstalk via mitochondria-associated membranes (MAMs), are critical in IR. However, a disruption in ER homeostasis might trigger ER stress and activate the unfolded protein response (UPR), culminating in a cellular adaptive mechanism. A dysregulation in this response contributes to lipid accumulation, inflammation, impaired insulin biosynthesis, and β-cell apoptosis. Simultaneously, altered MAM integrity disrupts calcium signalling, mitochondrial metabolism, and ER-mitochondria crosstalk, further aggravating IR across tissues, including liver, muscle, β-cells, and brain. Thus, UPR dysregulation and MAM perturbations represent a mechanistic nexus linking IR, T2D, and cancer. Understanding how these processes intersect might help in uncovering promising therapeutic avenues targeting ER stress, restoring MAM integrity, modulating UPR signalling, and thereby improving insulin sensitivity, mitigating metabolic disease and oncogenic risk.